Micronutrient supplementation in children and adults with HIV infection

James JH Irlam; Marianne ME Visser; Nigel N Rollins; Nandi Siegfried

doi:10.1002/14651858.CD003650.pub2

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Analysis 1.1

Comparison 1 Vitamin A / beta‐carotene vs placebo to adults, Outcome 1 CD4 count >=3 months follow‐up.

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Analysis 1.2

Comparison 1 Vitamin A / beta‐carotene vs placebo to adults, Outcome 2 CD8 count >= 3 months follow‐up.

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Analysis 1.3

Comparison 1 Vitamin A / beta‐carotene vs placebo to adults, Outcome 3 Viral load at < 3 months follow‐up.

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Analysis 1.4

Comparison 1 Vitamin A / beta‐carotene vs placebo to adults, Outcome 4 Mean bodyweight.

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Analysis 1.5

Comparison 1 Vitamin A / beta‐carotene vs placebo to adults, Outcome 5 Karnofsky score.

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Analysis 2.1

Comparison 2 Other micronutrients vs placebo to adults, Outcome 1 Mortality (all cause) by 48 weeks.

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Analysis 2.2

Comparison 2 Other micronutrients vs placebo to adults, Outcome 2 Mortality by 48 weeks (baseline CD4 < 200).

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Analysis 2.3

Comparison 2 Other micronutrients vs placebo to adults, Outcome 3 Mortality by 48 weeks (baseline CD4 >= 200).

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Analysis 2.4

Comparison 2 Other micronutrients vs placebo to adults, Outcome 4 Mortality by 48 weeks (baseline CD4 < 100).

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Analysis 2.5

Comparison 2 Other micronutrients vs placebo to adults, Outcome 5 Mortality by 48 weeks (baseline CD4 >=100).

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Analysis 2.6

Comparison 2 Other micronutrients vs placebo to adults, Outcome 6 New AIDS ‐defining infections.

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Analysis 2.7

Comparison 2 Other micronutrients vs placebo to adults, Outcome 7 New HIV‐associated infections.

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Analysis 2.8

Comparison 2 Other micronutrients vs placebo to adults, Outcome 8 New other infections.

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Analysis 2.9

Comparison 2 Other micronutrients vs placebo to adults, Outcome 9 Recurrent HIV‐associated infections.

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Analysis 2.10

Comparison 2 Other micronutrients vs placebo to adults, Outcome 10 Recurrent other infections.

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Analysis 2.11

Comparison 2 Other micronutrients vs placebo to adults, Outcome 11 Hospital admissions for all conditions.

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Analysis 2.12

Comparison 2 Other micronutrients vs placebo to adults, Outcome 12 Mean number of hospitalisations (OIs, HIV‐related, psychiatric) per patient.

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Analysis 2.13

Comparison 2 Other micronutrients vs placebo to adults, Outcome 13 Number of patients hospitalised for all conditions.

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Analysis 2.14

Comparison 2 Other micronutrients vs placebo to adults, Outcome 14 Patients hospitalised for OIs, HIV‐related conditions and psychiatric disorders.

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Analysis 2.15

Comparison 2 Other micronutrients vs placebo to adults, Outcome 15 Decline in CD4 counts > 50 cells per cubic mm after 12 months.

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Analysis 2.16

Comparison 2 Other micronutrients vs placebo to adults, Outcome 16 Lowered plasma selenium levels (< 135 microg/L) after 12 months.

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Analysis 2.17

Comparison 2 Other micronutrients vs placebo to adults, Outcome 17 Change in HIV viral load over 3 months.

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Analysis 2.18

Comparison 2 Other micronutrients vs placebo to adults, Outcome 18 Mortality (all cause) by 48 weeks.

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Analysis 2.19

Comparison 2 Other micronutrients vs placebo to adults, Outcome 19 Mortality by 48 weeks (baseline CD4 < 200).

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Analysis 2.20

Comparison 2 Other micronutrients vs placebo to adults, Outcome 20 Mortality by 48 weeks (baseline CD4 >= 200).

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Analysis 2.21

Comparison 2 Other micronutrients vs placebo to adults, Outcome 21 Mortality by 48 weeks (baseline CD4 < 100).

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Analysis 2.22

Comparison 2 Other micronutrients vs placebo to adults, Outcome 22 Mortality by 48 weeks (baseline CD4 >=100).

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Analysis 3.1

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 1 CD4 < 3 months.

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Analysis 3.2

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 2 CD4 >= 3 months.

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Analysis 3.3

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 3 CD4 difference (< 3 months).

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Analysis 3.4

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 4 CD4 difference (>= 3 months).

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Analysis 3.5

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 5 CD8 < 3 months.

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Analysis 3.6

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 6 CD8 >= 3 months.

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Analysis 3.7

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 7 CD8 difference (< 3 months).

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Analysis 3.8

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 8 CD8 difference (>= 3 months).

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Analysis 3.9

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 9 Total maternal weight gain.

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Analysis 3.10

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 10 Maternal weight gain in third trimester.

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Analysis 3.11

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 11 Progression to stage 4 or death from AIDS‐related causes.

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Analysis 3.12

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 12 Death from AIDS‐related causes.

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Analysis 3.13

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 13 Progression to stage 4 disease.

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Analysis 3.14

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 14 Progression to stage 3 disease or higher.

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Analysis 3.15

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 15 HIV‐related complications: thrush.

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Analysis 3.16

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 16 HIV‐related complications: gingival erythema.

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Analysis 3.17

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 17 HIV‐related complications: angular cheilitis.

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Analysis 3.18

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 18 HIV‐related complications: oral ulcer.

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Analysis 3.19

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 19 HIV‐related complications: reported mouth and throat ulcers.

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Analysis 3.20

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 20 HIV‐related complications: painful tongue or mouth.

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Analysis 3.21

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 21 HIV‐related complications: difficult or painful swallowing.

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Analysis 3.22

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 22 HIV‐related complications: nausea and vomiting.

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Analysis 3.23

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 23 HIV‐related complications: diarrhoea.

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Analysis 3.24

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 24 HIV‐related complications: dysentery.

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Analysis 3.25

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 25 HIV‐related complications: fatigue.

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Analysis 3.26

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 26 HIV‐related complications: rash.

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Analysis 3.27

Comparison 3 Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes], Outcome 27 HIV‐related complications: acute upper respiratory tract infection.

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Analysis 4.1

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 1 Foetal death (miscarriage+stillbirth).

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Analysis 4.2

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 2 Total mortality by 24 months including foetal deaths.

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Analysis 4.3

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 3 Mortality by 24 months among all live births.

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Analysis 4.4

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 4 Mortality by 24 months among HIV‐infected live births.

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Analysis 4.5

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 5 Mortality by 24 months among HIV‐infected infants at 6 weeks of age.

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Analysis 4.6

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 6 Mean birthweight.

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Analysis 4.7

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 7 Birthweight < 2000 g.

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Analysis 4.8

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 8 Birthweight < 2500 g.

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Analysis 4.9

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 9 Preterm birth (<37 weeks).

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Analysis 4.10

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 10 Severe preterm birth (<34 weeks).

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Analysis 4.11

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 11 Small for gestational age.

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Analysis 4.12

Comparison 4 Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes], Outcome 12 CD4 count >= 3 months.

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Analysis 5.1

Comparison 5 Vitamin A vs placebo to children, Outcome 1 All‐cause mortality.

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Analysis 5.2

Comparison 5 Vitamin A vs placebo to children, Outcome 2 All‐cause morbidity.

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Analysis 5.3

Comparison 5 Vitamin A vs placebo to children, Outcome 3 Diarrhoeal morbidity.

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Analysis 5.4

Comparison 5 Vitamin A vs placebo to children, Outcome 4 Persistent diarrhoea (>= 7 days).

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Analysis 5.5

Comparison 5 Vitamin A vs placebo to children, Outcome 5 Lower respiratory tract infections (LRTI).

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Analysis 5.6

Comparison 5 Vitamin A vs placebo to children, Outcome 6 Hospitalised for diarrhoea.

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Analysis 5.7

Comparison 5 Vitamin A vs placebo to children, Outcome 7 Hospitalised for LRTI.

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Analysis 5.8

Comparison 5 Vitamin A vs placebo to children, Outcome 8 Mean change in viral load after influenza vaccination.

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Comparison 1. Vitamin A / beta‐carotene vs placebo to adults

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CD4 count >=3 months follow‐up Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2 CD8 count >= 3 months follow‐up Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3 Viral load at < 3 months follow‐up Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4 Mean bodyweight Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5 Karnofsky score Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

Comparison 1. Vitamin A / beta‐carotene vs placebo to adults

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Comparison 2. Other micronutrients vs placebo to adults

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Mortality (all cause) by 48 weeks Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2 Mortality by 48 weeks (baseline CD4 < 200) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3 Mortality by 48 weeks (baseline CD4 >= 200) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4 Mortality by 48 weeks (baseline CD4 < 100) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5 Mortality by 48 weeks (baseline CD4 >=100) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6 New AIDS ‐defining infections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7 New HIV‐associated infections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8 New other infections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9 Recurrent HIV‐associated infections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10 Recurrent other infections Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11 Hospital admissions for all conditions Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12 Mean number of hospitalisations (OIs, HIV‐related, psychiatric) per patient Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

13 Number of patients hospitalised for all conditions Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

14 Patients hospitalised for OIs, HIV‐related conditions and psychiatric disorders Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

15 Decline in CD4 counts > 50 cells per cubic mm after 12 months Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

16 Lowered plasma selenium levels (< 135 microg/L) after 12 months Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

17 Change in HIV viral load over 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

18 Mortality (all cause) by 48 weeks Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

19 Mortality by 48 weeks (baseline CD4 < 200) Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

20 Mortality by 48 weeks (baseline CD4 >= 200) Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

21 Mortality by 48 weeks (baseline CD4 < 100) Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

22 Mortality by 48 weeks (baseline CD4 >=100) Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

Comparison 2. Other micronutrients vs placebo to adults

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Comparison 3. Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 CD4 < 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

2 CD4 >= 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

3 CD4 difference (< 3 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

4 CD4 difference (>= 3 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

5 CD8 < 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

6 CD8 >= 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7 CD8 difference (< 3 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

8 CD8 difference (>= 3 months) Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

9 Total maternal weight gain Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

10 Maternal weight gain in third trimester Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

11 Progression to stage 4 or death from AIDS‐related causes Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

12 Death from AIDS‐related causes Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

13 Progression to stage 4 disease Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

14 Progression to stage 3 disease or higher Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

15 HIV‐related complications: thrush Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

16 HIV‐related complications: gingival erythema Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

17 HIV‐related complications: angular cheilitis Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

18 HIV‐related complications: oral ulcer Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

19 HIV‐related complications: reported mouth and throat ulcers Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

20 HIV‐related complications: painful tongue or mouth Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

21 HIV‐related complications: difficult or painful swallowing Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

22 HIV‐related complications: nausea and vomiting Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

23 HIV‐related complications: diarrhoea Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

24 HIV‐related complications: dysentery Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

25 HIV‐related complications: fatigue Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

26 HIV‐related complications: rash Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

27 HIV‐related complications: acute upper respiratory tract infection Show forest plot	1		Hazard ratio (Random, 95% CI)	Subtotals only

Comparison 3. Multivitamins vs no multivitamins to pregnant and lactating women [maternal outcomes]

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Comparison 4. Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes]

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Foetal death (miscarriage+stillbirth) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2 Total mortality by 24 months including foetal deaths Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3 Mortality by 24 months among all live births Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4 Mortality by 24 months among HIV‐infected live births Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5 Mortality by 24 months among HIV‐infected infants at 6 weeks of age Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6 Mean birthweight Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

7 Birthweight < 2000 g Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8 Birthweight < 2500 g Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

9 Preterm birth (<37 weeks) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

10 Severe preterm birth (<34 weeks) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

11 Small for gestational age Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

12 CD4 count >= 3 months Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

Comparison 4. Multivitamins vs no multivitamins to pregnant and lactating women [child outcomes]

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Comparison 5. Vitamin A vs placebo to children

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

2 All‐cause morbidity Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3 Diarrhoeal morbidity Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

4 Persistent diarrhoea (>= 7 days) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

5 Lower respiratory tract infections (LRTI) Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

6 Hospitalised for diarrhoea Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

7 Hospitalised for LRTI Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

8 Mean change in viral load after influenza vaccination Show forest plot	1		Mean Difference (IV, Random, 95% CI)	Subtotals only

Comparison 5. Vitamin A vs placebo to children

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